Prior Art on Compound of Formula I
European Patent 193926 claims phenyl carbamate compounds and their pharmacologically acceptable salts for use as pharmaceutical agents producing anticholinesterase activity in the central nervous system. The patent discloses the process for the preparation of the title phenyl carbamate compounds involving reaction of hydroxyphenyl-substituted alkyl amines with appropriate isocyanates or carbamoyl halides. The process using isocyanates involves the use of benzene as a solvent. Isocyanates such as lower alkyl isocyanates are hazardous to handle due to their toxic and non-volatile nature. The other alternative reported is the use of carbamoyl halides along with reactive bases like sodium hydride, to prepare the carbamates. The carbamoyl halides are not easy to handle at industrial scales and involve safety hazards. The use of a reactive base like sodium hydride on an industrial scale is hazardous and operationally non-user friendly due to its pyrophoric and reactive nature. More importantly, as per the process, 200% excess of the reagent is required for the reaction, and absolutely anhydrous conditions need to be employed. The excess reagent is quenched with water. This process would cause uncontrollable exothermicity at an industrial scale, and it is also possible that the highly alkaline conditions resulting from the formation of sodium hydroxide during the quenching of excess sodium hydride would cause degradation of the product formed, the degradation being more extensive at reaction temperatures above ambient temperature.
The prior art employs reagents like isocyanates and carbamoyl halides to make carbamates and in the process solvents like benzene, in case of isocyanates, or anhydrous reaction conditions with the use of sodium hydride, are necessary to carry out the reaction. Performing these reactions on a large scale entails several safety measures, in terms of storage, handling and quenching excess of reagents, as well as the poor quality of the end product.
The present invention avoids the above mentioned drawbacks by providing a process for the preparation of compound of formula I,
wherein R1 is hydrogen, linear, branched or cyclic lower alkyl, cyclohexyl, allyl, propargyl or benzyl; R2 is hydrogen, methyl, ethyl or propyl; or R1 and R2 together with the nitrogen to which they are attached form a cyclic moiety of three to eight-membered ring, with or without a hetero atom like nitrogen or oxygen; R3 is hydrogen or lower alkyl; R4 and R5 are the same or different and each is a lower alkyl; comprising reacting compound of formula II,
wherein R3, R4 and R5 are as defined above, with compound of formula III,
wherein R1 and R2 are as defined above, in the presence of a base.Prior Art on Compound of Formula II
The present invention also provides a novel process for the preparation of 1-(3-hydroxyphenyl)alkyl-(N-mono/dialkyl)amine, compound of formula II.
The process for the preparation of 1-(3-hydroxyphenyl)alkyl-(N-mono/dialkyl)amine of formula I from 1-(3-methoxyphenyl)alkyl-(N-mono/dialkyl)amine by demethylation is known in the prior art. For example, J. Labelled Comp. And Radiopharm. 1997, 39(8), 651-668 reports a process involving a final step of demethylation of the methoxy function of 1-(3-methoxyphenyl)ethyl-(N,N-dimethyl)amine, using hydrobromic acid in the presence of hexadecyltributyl phosphonium bromide as the phase transfer catalyst, to yield 1-(3-hydroxyphenyl)ethyl-(N,N-dimethyl)amine. The use of hydrobromic acid, with or without the use of phase transfer catalysts, for demethylation of the methoxy function has a disadvantage in that the quality of the final product is not satisfactory due to a number of impurities formed in the reaction. Also, the process involves the use of expensive reagents such as phase transfer catalysts.
European Patent No. 359647 discloses a process for the preparation of morphinane derivatives involving demethylation of 3-methoxylated compounds using a sulphonic acid chosen from among methanesulphonic acid and trifluoromethanesulphonic acid, in the presence of a sulphide. However, the disadvantage of using sulfonic acid such as methanesulfonic acid is that it is a very expensive reagent and large volumes of the acid are required to isolate the final product.
There exists a need for a process for the preparation of 1-(3-hydroxyphenyl)alkyl-(N-mono/dialkyl)amine, compound of formula II, such that the process utilizes easily available starting materials, simple reagents and standard reaction conditions. The process should result in 1-(3-hydroxyphenyl)alkyl-(N-mono/dialkyl)amines of satisfactory quality, in a satisfactory yield.